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Smokers are much more likely to develop lung cancer than nonsmokers  that has been a scientific truism for decades. But what about the 80% of smokers who don't develop lung cancer? Are they just the lucky ones? A trio of new studies suggests that the explanation for why they escape the disease may lie partly in their genes.

Three new reports by research teams in the U.S., Europe and Iceland have identified, for the first time, specific gene variants that appear to make some smokers and former smokers more susceptible than others to cancer. The two variants  or differences in a single nucleotide  exist in about 34% of the population and occur in genes in the same region of the long arm of chromosome 15. Those genes code for nicotinic acetylcholine receptors, cell-surface proteins that selectively bind to nicotine molecules. Once nicotine attaches to these receptors, a series of changes in the cells is triggered: in the lungs, for example, cells are pushed into rapid, uncontrolled growth, which promotes the growth of new feeder blood vessels, creating, in turn, a particularly hospitable environment for cancer tumors. The new studies, published in Nature and Nature Genetics, found that smokers who possessed one copy of either variant were 28% more likely to develop lung cancer, while those with two copies were at a stunning 81% increased risk for the disease.

"These are very interesting and potentially very, very important findings," says Dr. Norman Edelman, chief medical officer of the American Lung Association. "They put nicotine front and center in smoking-related diseases, including lung cancer."

What sets the new research apart from previous studies of lung-cancer genes is the researchers' effort to separate the influence of genetic variants on cancer risk from the impact of years of smoking. One study  led by scientists at DeCODE Genetics in Iceland  found that smokers who had one copy of either of the genetic variants smoked more per day than others. The findings suggest that the specific gene variants may increase nicotine addiction, making smokers less likely to quit smoking, and, therefore, increasing their risk of cancer.

The other two studies examined the cancer risk and smoking habits
of current and former smokers, with and without cancer, with a carefully
matched control group of never-smokers. While the variants were associated with an increased risk of lung cancer in smokers, that genetic predisposition is not destiny. In the U.S.-based study, led by Christopher Amos, an epidemiologist at the M.D. Anderson Cancer Center in Houston, people who never smoked but still had the genetic variants showed no increased risk of lung cancer, which suggests that nicotine might be necessary to trigger the tumor-building process  and that smokers with this particular genetic profile are only at greater risk for developing lung cancer if they expose their airways to nicotine.

Amos's study included only a small number of nonsmokers, however; the European study, which included a larger sample, did find a slightly higher risk of lung cancer in nonsmokers with the genetic variants. That could explain some of the genetic risk that leads to lung cancer in the 10% of men and 20% of women who develop the disease every year despite never having lit up.

The new results allow researchers to construct a better picture of how cigarette smoking affects the body, and how the active agents in cigarettes, including nicotine, alter the normal growth and development of cells in the lung. That could lead to improved and individualized smoking-cessation drugs and programs, which are currently successful only 25% of the time. "It could be that we need to tailor how we get people to quit," says Amos. For some, behavior modification may be sufficient; perhaps others will need targeted nicotine-blocking drugs that can fight any genetic bias toward addiction.

Whatever the new weapons against smoking addiction may be, the authors
stress that we already know the best way to prevent it  by not smoking
in the first place. Cancer risk aside, smoking also increases the risk of emphysema and heart disease; what's more, smokers without the genetic variants are not at all protected from developing lung cancer or any other smoking-related disease. "Nothing in these papers should give people comfort in terms of continuing smoking," says Edelman, "even after they have their genetic profiles looked at. But if we can use this information to develop better approaches to smoking cessation, then we can reduce the amount of smoking-related disease enormously."